This is generally in the field of treatment or prevention of acute renal failure due to prerenal causes by administration of an antagonist of adenosine signaling, such as aminophylline, and of treatment of kidney transplants (renal allografts) to prolong survival of the graft during cold ischemia and immediately after transplantation.
Acute kidney failure occurs when illness, infection, or injury damages the kidneys resulting in a rapid decline in the kidneys' ability to clear the blood of toxic substances. Temporarily, the kidneys cannot adequately remove fluids and wastes from the body or maintain the proper level of certain kidney-regulated chemicals leading to an accumulation of metabolic waste products, such as urea, in the blood.
Acute kidney failure can result from any condition that decreases the blood supply to the kidneys (prerenal acute renal failure), obstructs the flow of urine after it has left the kidneys (postrenal acute renal failure), or injures the kidneys themselves (intra-renal acute renal failure). Toxic substances that may damage the kidneys include drugs, poisons, crystals precipitated in the urine, and antibodies that react against the kidneys. Symptoms depend on the severity of kidney failure, its rate of progression, and its underlying cause but can include anemia, bad breath, bone and joint problems, edema, frequent urination, hematuria, headaches, hypertension, fatigue, itching, lower back pain and nausea, and ultimately, death.
The condition that leads to the kidney damage often produces serious symptoms unrelated to the kidneys. For example, high fever, shock, heart failure, and liver failure may occur before kidney failure and may be more serious than any of the symptoms of kidney failure. Some of the conditions that cause acute kidney failure also affect other parts of the body. For example, Wegener's granulomatosis, which damages blood vessels in the kidneys, may also damage blood vessels in the lungs, causing a person to cough up blood. Skin rashes are typical of some causes of acute kidney failure, including polyarteritis, systemic lupus erythematosus, and some toxic drugs. Hydronephrosis can cause acute kidney failure resulting from obstruction of urine flow.
Acute kidney failure can be caused by many different illnesses, injuries, and infections. These conditions fall into three main categories: prerenal, postrenal, and intrarenal conditions. Prerenal conditions do not damage the kidney, but can cause diminished kidney function. They are by far the most common cause of acute renal failure, and include dehydration, hemorrhage, septicemia, heart failure, liver failure, and burns. Approximately 95% of acute renal failure in the hospital is prerenal, due to decreased renal blood flow due to intravascular volume depletion or cardiac pump failure. A common cause of prerenal acute renal failure outside the hospital is rhabdomyolysis: muscle breakdown caused by a crush injury, as in an earthquake, or prolonged marching by soldiers. In out-of-hospital situations such as these, access to a kidney dialysis machine is often unavailable.
Postrenal conditions cause kidney failure by obstructing the urinary tract and include inflammation of the prostate gland in men (prostatitis), enlargement of the prostate gland (benign prostatic hypertrophy), bladder or pelvic tumors, and kidney stones (calculi). Intrarenal conditions involve kidney disease or direct injury to the kidneys. These conditions include lack of blood supply to the kidneys (ischemia), use of radiocontrast agents in patients with kidney problems, drug abuse or overdose, long-term use of nephrotoxic medications, acute inflammation of the glomeruli, or filters, of the kidney (glomerulonephritis), kidney infections (pyelitis or pyelonephritis).
Acute kidney failure and its immediate complications can often be treated successfully. The survival rate ranges from less than 50 percent for people who have failure of several organs to about 90 percent for those who have decreased blood flow to the kidneys because body fluids have been lost through bleeding, vomiting, or diarrhea. Treatment for acute kidney failure varies. Treatment is directed to the underlying, primary medical condition that has triggered kidney failure. Prerenal conditions may be treated with replacement fluids given through a vein, diuretics, blood transfusion, or medications. Postrenal conditions and intrarenal conditions may require surgery and/or medication.
Often, simple but meticulous treatment is all that is required for the kidneys to heal themselves. In addition to glucose or highly concentrated carbohydrate feedings, certain amino acids are given orally or intravenously to maintain adequate protein levels. The intake of all substances that are eliminated through the kidneys, including many drugs such as digoxin and some antibiotics, must be strictly limited. Because antacids that contain aluminum bind phosphorus in the intestines, they may be given to prevent the blood phosphorus level from rising too high. Sodium polystyrene sulfonate is sometimes given orally or rectally to treat a high blood level of potassium.
Kidney failure may be so severe that dialysis is needed to prevent serious harm to other organs and to control symptoms. In these cases, dialysis is started as soon as possible after diagnosis. Dialysis may be needed only until the kidneys recover their function, usually in several days to several weeks. However, if the kidneys are too badly damaged to recover, dialysis may be needed indefinitely, unless kidney transplantation is performed. Dialysis for acute renal failure, however, is extremely expensive and carries a high mortality rate (50%) that has remained unchanged despite advances in dialysis. The natural course of oliguric acute renal failure is to progress to acute tubular necrosis, a state of near-total kidney failure that requires renal replacement therapy.
Acute renal failure (ARF) continues to defy efforts at therapy, and carries a 50% mortality. It has long been known to involve renal vasoconstriction, having been called “vasomotor nephropathy” since the 1960's (Myers, et al., N.E.J. Med. 314:97-105, 1986). Over several decades. Dr. Franklin Epstein has documented the role of ischemia, especially of the medullary thick ascending limb, in the pathogenesis of ARF (Epstein, et al., Hospital Practice Jan. 15, 1988: 171-194, passim). ARF is a clinical syndrome marked by an abrupt and sustained decrease in renal function which occurs in response to an ischemic or nephrotoxic insult, and which is not immediately reversible upon correction of the precipitation event. ARF can lead to life-threatening complications such as uremia, sepsis, gastrointestinal hemorrhage, and central nervous system dysfunction. It is associated with a high mortality rate and may be a major factor in determining the outcome of multi-organ failure. For example, in one study of similarly traumatized patients, those who developed acute renal failure had a five-fold higher mortality rate than those who did not. A high percentage of patients with ARF will require invasive life-sustaining therapy with dialysis—with its associated risk of bleeding complications, arrhythmias, hypotension, additional cost, and negative impact on quality of life. ARF is also associated with prolongation of hospitalization, and significantly complicates the care of severely ill patents by limiting the fluids and medications that may be administered to them. In addition, a significant number of patients surviving ATN (acute tubular necrosis) are left with residual renal insufficiency.
At present there is no therapy available for the treatment of ATN other than supportive care. Physicians frequently use diuretics such as furosemide or mannitol, and/or “renal dose” dopamine empirically with the hope of increasing urine output, but none of these agents have been shown to improve renal function significantly nor decrease the morbidity and mortality, as well as the expense associated with this disease. Recovery from ATN may last from weeks to months, in proportion to a patient's age. In the meantime, acute dialysis is required on at least a trice-weekly basis. It would therefore represent a considerable savings, both in health care dollars as well as lives, if ATN could be quickly aborted pharmacologically.
A method of treatment that can prevent damage during acute renal failure is needed.
It is therefore an object of the present invention to provide a treatment to prevent or treat acute renal failure.
It is another object of the present invention to provide a treatment to enhance viability of kidneys for transplant purposes.